Author: [email protected]

KANCERA REPORTS POSITIVE RESULTS FOR FRACTALKINE BLOCKER KAN0440567 IN PRECLINICAL MODELS OF PAIN CAUSED BY ANTI-CANCER DRUGS

On December 19, 2016 Kancera AB (publ) reported that the drug candidate KAN0440567 quickly and effectively counteracts the kind of pain that results from chemotherapy and that often prevents effective treatment of cancer (Press release, Kancera, DEC 19, 2016, View Source [SID1234517128]). The results also indicate that the Kancera drug candidate inhibits the development of the nerve damage that causes pain.

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Kancera, in collaboration with Professor Malcangio at King’s College, London, showed that oral treatment with the fractalkine blocker KAN0440567 counteracts pain caused by vincristine. Vincristine is a chemotherapy agent used to treat cancers such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), Hodgkin’s disease, neuroblastoma and small cell lung cancer.

Pain resulting from chemotherapy often leads to cancer treatment needing to be reduced in intensity or being interrupted before the desired results are achieved (1). Every year about 1.7 million patients are treated with chemotherapy in the United States, Europe and Japan (2). Approximately 80% (3) of these are affected by nerve injury and subsequent pain and a significant proportion of these will have lasting problems that prevent a normal life. Today there is no effective treatment for this type of nerve damage.

In the Kancera study mice were treated with vincristine twice daily for five days, resembling the clinical protocol that can lead to nerve injury and pain. Oral treatment with KAN0440567, 125 mg/kg twice daily, effectively reduced the onset of this pain. From day one the effect was evident in the KAN0440567-treated animals and on days two to five pain was significantly lower than the control group. The study also showed that KAN0440567 did not affect sensitivity to being touched in the control animals, which supports the idea that the Kancera drug candidate specifically inhibits development of nerve damage.

If these effects are also achieved under clinical conditions, KAN0440567 could contribute to more effective cancer treatment since the desired dosage of chemotherapy can be maintained longer with less side effects in the form of nerve damage. Furthermore, reduced long-lasting nerve problems after successful cancer treatment would result in more patients being able to return to a normal life.

What makes KAN0440567 unique is that it works by preventing a special group of immune cells (monocytes) from infiltrating healthy tissue and causing damage, while other parts of the immune system maintain their protective ability. Thus, KAN440567 is likely to be effective in several inflammatory diseases, cancer and pain, without seriously affecting the immune system in general.

1. Windebank AJ and Grisold W (2008) J Per Nerv Syst 13: 27-46
2. IMS
3. Sisignano, M. et al. (2014) Nat Rev Neurol 10, 694–707

About the Fractalkine project Fractalkine is an immune regulatory factor, a so-called chemokine, that sends signals via the CX3CR1 receptor, also called G-protein coupled receptor 13 (GPCR13). The level of fractalkine and its receptor, CX3CR1 has been shown to be elevated in many inflammatory diseases, cancer and in chronic pain conditions. Kancera’s drug candidate KAN0440567 is the furthest developed drug candidate against CX3CR1 and has been shown to be effective against inflammation and pain in several preclinical disease models. Kancera is now preparing the project for clinical studies. In the healthy individual, Fractalkine and its receptor regulate migration of immune cells from the blood capillary wall into areas where the immune system is needed. Animal studies show that Fractalkine’s receptor is not essential for survival and that important immune functions remain intact despite the lack of receptor.The body of research supports the overall hypothesis that CX3CR1 is more crucial to developing disease than to keeping the individual healthy. The basis for successful development of KAN0440567 lies in effectively addressing local inflammation while maintaining a healthy immune system.

Foundation Medicine Receives FDA Approval of FoundationFocus™ CDxBRCA as a Companion Diagnostic for Rubraca™ (rucaparib) for the Treatment of Women with Ovarian Cancer

On December 19, 2016 Foundation Medicine, Inc. (NASDAQ:FMI) reported that the U.S. Food and Drug Administration (FDA) has approved FoundationFocus CDxBRCA for use as a companion diagnostic to aid in identifying women with ovarian cancer for whom treatment with Rubraca (rucaparib), a therapy developed by Clovis Oncology, Inc., is being considered (Press release, Foundation Medicine, DEC 19, 2016, View Source [SID1234517130]). FoundationFocus CDxBRCA is an FDA-approved tissue-based, genomic assay that uniquely detects tumor BRCA1 and BRCA2 mutations (may include both germline (inherited) and somatic (acquired)) in ovarian cancer. FoundationFocus CDxBRCA may help identify more women who could benefit from Rubraca therapy as compared to conventional testing methods that only identify germline BRCA1/2 mutations. Germline-only BRCA1/2 testing identifies approximately half of all BRCA1/2 mutations.i,ii

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Rubraca is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated as monotherapy for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer who have been treated with two or more chemotherapies, and selected for therapy based on an FDA-approved companion diagnostic for Rubraca.

"These simultaneous approvals by the FDA represent a step forward for women with advanced ovarian cancer, an area where there is a tremendous need for effective therapeutic approaches and efficient ways to identify those most likely to respond to PARP inhibitor therapy," said Michael Pellini, M.D., chief executive officer of Foundation Medicine. "This approval also represents a significant milestone for Foundation Medicine, one that underscores the quality and value of our molecular information solutions to inform patient care and to accelerate and streamline the therapeutic development programs of our biopharmaceutical partners."

Foundation Medicine and Clovis Oncology closely collaborated on a regulatory strategy to develop FoundationFocus CDxBRCA in parallel with the development of Rubraca. Tissue samples taken from individuals with ovarian cancer who enrolled in rucaparib clinical trials were analyzed by Foundation Medicine utilizing comprehensive genomic profiling (CGP) to identify biomarkers associated with a response to therapy. These molecular signatures of response informed the development of FoundationFocus CDxBRCA, which was utilized in Clovis’ pivotal trial, ARIEL2, to identify patients and accelerate recruitment into the study. The companies filed concurrent pre-market approval (PMA) and new drug application (NDA) submissions with the FDA earlier this year.

With this FDA approval, FoundationFocus CDxBRCA is the first validated, tissue-based assay developed from the Quality Systems Regulations (QSR)-compliant version of Foundation Medicine’s CGP assay, providing uniform analysis of all BRCA1/2 coding exons.

Dr. Pellini continued, "FDA approval of our first companion diagnostic assay also represents an important advance in our efforts to utilize our rigorously validated CGP approach to deliver a universal companion diagnostic assay. We believe this approach may enable the efficient delivery of personalized cancer care by eliminating the guesswork for physicians through a comprehensive view of companion diagnostic claims, as well as potential treatment options based on guidelines, peer reviewed literature and clinical trials."

As part of the company’s effort to develop a universal companion diagnostic, earlier this year, Foundation Medicine announced that FoundationOne, the company’s CGP assay for solid tumors, was accepted by the FDA and the Centers for Medicare and Medicaid Services (CMS) for Parallel Review. The FDA also granted Foundation Medicine’s request for review as part of its Expedited Access Pathway for breakthrough devices. If approved, FoundationOne would be an FDA-approved CGP assay that incorporates multiple companion diagnostics to support precision medicine in oncology, including an indication for use as a companion diagnostic across a diverse range of solid tumors, which is anticipated to include ovarian cancer.

More than 22,000 women will potentially be diagnosed with ovarian cancer in the U.S. during 2016.iii Ovarian cancer is the leading cause of female gynecologic cancer-related deathsiv and one in four women with ovarian cancer have a germline or somatic BRCA mutation.ii

About FoundationFocus CDxBRCA

Intended Use: FoundationFocus CDxBRCA is a next generation sequencing test for qualitative detection of BRCA1 and BRCA2 (BRCA1/2) alterations in formalin-fixed paraffin-embedded (FFPE) ovarian tumor tissue. The FoundationFocus CDxBRCA assay detects sequence alterations in BRCA1/2 genes. Results of the test are used as an aid in identifying ovarian cancer patients for whom treatment with Rubraca (rucaparib) is being considered. If a patient is positive for any of the deleterious alterations specified in the BRCA1/2 classification, the patient may be eligible for treatment with Rubraca. This assay is to be performed at Foundation Medicine, Inc., a single laboratory site located at 150 Second Street, Cambridge, MA 02141. For more information about FoundationFocus CDxBRCA assay, visit View Source

Clovis Oncology Announces FDA Accelerated Approval of RUBRACA™ (rucaparib) for the Monotherapy Treatment of Advanced Ovarian Cancer in Women with Deleterious Germline or Somatic BRCA Mutations Treated with Two or More Chemotherapies

On December 19, 2016 Clovis Oncology, Inc. (NASDAQ:CLVS) reported that the U.S. Food and Drug Administration (FDA) has approved Rubraca (rucaparib) tablets as monotherapy for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer, who have been treated with two or more chemotherapies, and selected for therapy based on an FDA-approved companion diagnostic for Rubraca (Press release, Clovis Oncology, DEC 19, 2016, View Source [SID1234517133]). Rubraca’s indication is approved under the FDA’s accelerated approval program, and is based on objective response rate and duration of response results from two multicenter, single-arm, open-label clinical trials, Study 10 and ARIEL2 Parts 1 and 2. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. The ARIEL3 maintenance confirmatory study has completed enrollment and the ARIEL4 treatment confirmatory study is open for enrollment. Warning and precautions include Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML). Please see additional warnings and precautions and Select Important Safety Information below.

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This Smart News Release features multimedia. View the full release here: View Source

"Recurrent ovarian cancer remains one of the most difficult cancers to treat and for so many years, medical advances in this space have been limited," said Robert L. Coleman, MD, Professor & Deputy Chairman, Vice Chair, Clinical Research, Ann Rife Cox Chair in Gynecology, Department of Gynecologic Oncology and Reproductive Medicine at University of Texas MD Anderson Cancer Center in Houston and one of the Principal Investigators in the ARIEL clinical trial program. "Today’s approval of Rubraca for the treatment of advanced ovarian cancer demonstrates the value of treatment with PARP inhibitors and represents an important advance for women diagnosed with either germline or somatic BRCA-mutated tumors who have been treated with two or more chemotherapies."

"We believe that today’s approval of Rubraca provides an important new therapy for advanced ovarian cancer patients with a germline or somatic mutation of BRCA after two or more chemotherapies," said Patrick J. Mahaffy, CEO and President of Clovis Oncology. "We look forward to launching Rubraca with the support of our established U.S. commercial and medical affairs organizations and bringing this much-needed precision medicine to women with advanced ovarian cancer as quickly as possible."

"NOCC commends Clovis Oncology for its commitment to bringing a new treatment option to women living with ovarian cancer, the deadliest cancer of the female reproductive system. All too often, women are diagnosed when the disease is far advanced, leaving them with few viable treatment options," said David Barley, Chief Executive Officer, National Ovarian Cancer Coalition. "The development and FDA approval of therapies for use in third-line is a promising step forward for the tens of thousands of women who will battle ovarian cancer in their lifetime."

"Ovarian cancer is one of the most difficult cancers to detect. For this reason, most women who develop ovarian cancer are diagnosed with advanced disease," said Sue Friedman, DVM, Executive Director of Facing Our Risk of Cancer Empowered. "There is a tremendous need for new ways to treat women with advanced ovarian cancer and ways to find those women who will respond to therapies such as PARP inhibitors. PARP inhibitors, like Rubraca, represent an exciting advancement for appropriate patients."

The Rubraca NDA filing received Priority Review and was reviewed and approved under FDA’s Accelerated Approval program. These programs allow for earlier approval of drugs that treat serious conditions and that fill an unmet medical need. The application was based on objective response rate and duration of response results from two multicenter, single-arm, open-label clinical trials, Study 1 (Study 10, NCT01482715) and Study 2 (ARIEL2 Parts 1 and 2, NCT01891344), in women with advanced BRCA-mutant ovarian cancer who had progressed after two or more prior chemotherapies. All 106 patients received Rubraca orally 600 mg twice daily as monotherapy until disease progression or unacceptable toxicity. Objective response rate (ORR) and duration of response (DOR) were assessed by the investigator and independent radiology review (IRR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

Clovis partnered with Foundation Medicine, Inc. to co-develop a companion diagnostic test, the FDA approved FoundationFocusTM CDxBRCA, to select patients for Rubraca treatment. FoundationFocus CDxBRCA is a tissue-based, genomic assay that detects tumor BRCA1 and BRCA2 mutations (germline and/or somatic) in ovarian cancer.

Efficacy and safety results from the U.S. Prescribing Information are summarized below:

Overall Response and Duration of Response in Patients with BRCA-mutant Ovarian Cancer Who Received 2 or More Chemotherapies in Study 1 and Study 2



Investigator-assessed
N=106
Objective Response Rate (95% CI) 54% (44, 64)
Complete Response 9%
Partial Response 45%
Median DOR in months (95% CI) 9.2 (6.6, 11.6)

Response assessment by IRR was 42% (95% CI: 32, 52), with a median DOR of 6.7 months (95% CI: 5.5, 11.1). Investigator-assessed ORR was 66% (52/79; 95% CI: 54, 76) in platinum-sensitive patients, 25% (5/20; 95% CI: 9, 49) in platinum-resistant patients, and 0% (0/7; 95% CI: 0, 41) in platinum-refractory patients. ORR was similar for patients with a BRCA1 gene mutation or BRCA2 gene mutation.

The overall safety evaluation of Rubraca 600 mg twice daily as monotherapy is based on data from 377 patients with ovarian cancer treated in two open-label, single arm trials. The most common adverse reactions (≥ 20% of patients; Grade 1-4) were nausea, asthenia/fatigue, vomiting, anemia, constipation, dysgeusia, decreased appetite, diarrhea, abdominal pain, thrombocytopenia and dyspnea. The most common laboratory abnormalities (≥ 35% of patients; Grade 1-4) were increase in creatinine, increase in ALT, increase in AST, decrease in hemoglobin, decrease in lymphocytes, increase in cholesterol, decrease in platelets and decrease in absolute neutrophil count.

About Rubraca Connections

Rubraca will be available in the United States immediately. For those who are eligible, Clovis Oncology plans to offer programs through Rubraca Connections to support patients taking Rubraca. More information about Rubraca Connections is available at RubracaConnections.com or by calling 1-844-779-7707 between 8 am and 8 pm Eastern, Monday through Friday.

About RubracaTM (rucaparib)

Rubraca is a PARP inhibitor indicated as monotherapy for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer, who have been treated with two or more chemotherapies, and selected for therapy based on an FDA-approved companion diagnostic for Rubraca. Rubraca’s indication is approved under the FDA’s accelerated approval program based on objective response rate and duration of response, and is based on results from two multicenter, single-arm, open-label clinical trials. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Select Important Safety Information

There are no contraindications with Rubraca.

Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) was reported in 2 of 377 (0.5%) patients with ovarian cancer treated with Rubraca. The duration of Rubraca treatment prior to the diagnosis of MDS/AML was 57 days and 539 days. Both patients received prior treatment with platinum and other DNA damaging agents.

AML was reported in 2 (<1%) patients with ovarian cancer enrolled in ARIEL3, a blinded, randomized trial evaluating Rubraca versus placebo. One case of AML was fatal. The duration of treatment prior to the diagnosis of AML was 107 days and 427 days. Both patients had received prior treatment with platinum and other DNA damaging agents.

Do not start Rubraca until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1).

Monitor complete blood count testing at baseline and monthly thereafter. For prolonged hematological toxicities, interrupt Rubraca and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Rubraca.

Rubraca can cause fetal harm when administered to pregnant women based on its mechanism of action and findings from animal studies. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Rubraca.

Most common adverse reactions (≥ 20%; Grade 1-4) were nausea (77%), asthenia/fatigue (77%), vomiting (46%), anemia (44%), constipation (40%), dysgeusia (39%), decreased appetite (39%), diarrhea (34%), abdominal pain (32%), dyspnea (21%), and thrombocytopenia (21%).

Most common laboratory abnormalities (≥ 35%; Grade 1-4) were increase in creatinine (92%), increase in alanine aminotransferase (ALT) (74%), increase in aspartate aminotransferase (AST) (73%), decrease in hemoglobin (67%), decrease in lymphocytes (45%), increase in cholesterol (40%), decrease in platelets (39%), and decrease in absolute neutrophil count (35%).

Because of the potential for serious adverse reactions in breast-fed infants from Rubraca, advise lactating women not to breastfeed during treatment with Rubraca and for 2 weeks after the final dose.

Please see the U.S. Prescribing Information for full safety and efficacy or visit www.Rubraca.com for more information.

Threshold Pharmaceuticals and National Cancer Institute to Collaborate on Drug Candidate TH-3424

On December 19, 2016 Threshold Pharmaceuticals, Inc. (NASDAQ:THLD), a clinical-stage biopharmaceutical company developing novel therapies for cancer, reported that it has entered into a collaboration with the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), to study TH-3424, the company’s new drug candidate for the treatment of cancer (Press release, Threshold Pharmaceuticals, DEC 19, 2016, View Source [SID1234517126]). The collaboration will explore the effects of TH-3424 against T-cell acute lymphoblastic leukemia (T-ALL) xenograft cell lines with high AKR1C3 expression. The studies will be conducted through the NCI-funded Pediatric Preclinical Testing Consortium (PPTC). Under this collaboration, Threshold will supply TH-3424, and the NCI will fund the studies that will be conducted at the PPTC leukemia research program led by Professor Richard Lock of Children’s Cancer Institute (Sydney, Australia).

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TH-3424 is a novel, small-molecule compound invented at Threshold with potentially broad anticancer properties. TH-3424 is activated by the enzyme AKR1C3, which is over-expressed in a number of different cancers, to release a cytotoxic agent directly to the tumor. Preclinical results showed that TH-3424 is effective in a variety of human xenograft models of cancer, as initially presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in April 2016.

"TH-3424 is designed to be activated by AKR1C3 inside tumor cells and spare healthy tissue," said Barry Selick, Ph.D., CEO of Threshold Pharmaceuticals. "Evaluating this compound in collaboration with the NCI enables us to expand the scope of our investigations to better inform our strategy for potential future clinical studies for this molecule."

About TH-3424
TH-3424 is a small-molecule drug candidate being evaluated for the potential treatment of hepatocellular cancer (HCC), castrate resistant prostate cancer (CRPC), T-cell acute lymphoblastic leukemias (T-ALL), and other cancers expressing high levels of aldo-keto reductase family 1 member C3 (AKR1C3). Tumors overexpressing AKR1C3 can be resistant to radiation therapy and chemotherapy and immunotherapy. TH-3424 is a prodrug that selectively releases a potent DNA cross-linking agent in the presence of AKR1C3. Investigational New Drug (IND)-enabling toxicology studies are being done in collaboration with Ascenta Pharmaceuticals, Ltd.

Kite Pharma Announces Successful Defense of Roberts Patent and Intent to Appeal U.S. Patent and Trademark Office Decision on a Narrow Patent Focused on Select CD28 CAR-T Products

On December 19, 2016 Kite Pharma, Inc. (Nasdaq:KITE) reported several updates to its broad intellectual property portfolio relating to the use of chimeric antigen receptors (CARs) to harness the power of a patient’s immune cells (Press release, Kite Pharma, DEC 19, 2016, View Source [SID1234517123]). These updates include a recent U.S. Patent and Trademark Office (USPTO) decision concerning one narrow patent related to CAR products containing a pre-specified CD28 costimulatory domain, and a recent favorable result in a challenge at the USPTO to one of Kite’s important CAR-T patents, U.S. Patent Number 6,319,494.

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In August 2015, Kite preemptively filed a petition with the U.S. Patent and Trademark Office (USPTO) to institute an inter partes review (IPR) of U.S. Patent No. 7,446,190 owned by Sloan Kettering Institute for Cancer Research and licensed by Juno Therapeutics, Inc. The IPR was aimed at invalidating the ‘190 patent, which has a narrow scope directed to CAR products containing a pre-specified CD28 costimulatory domain. The USPTO’s recent ruling in this matter did not revoke the patent. However, Kite continues to believe the patent to be invalid and plans to appeal the USPTO decision to the U.S. Court of Appeals for the Federal Circuit. This patent does not have any counterpart patents outside of the United States.

The USPTO’s decision will have no impact on the timing of the rolling submission or review of the Biologics License Application for Kite’s lead product candidate, axicabtagene ciloleucel (KTE-C19), a potentially lifesaving investigational therapy that has demonstrated the most advanced utilization of the CD28 costimulatory domain in a CAR-T therapy to date. Axicabtagene ciloleucel is currently being developed for the treatment of CD19 positive B cell malignancies, including non-Hodgkin lymphoma and acute lymphoblastic leukemia.

Separately, Kite recently defeated an anonymous challenge filed against U.S. Patent Number 6,319,494, developed by Kite’s Senior Vice President of Discovery Research, Margo Roberts, Ph.D. and colleagues. This patent, which covers methods for treating a viral disease or malignancy using modified T cells that contain single-chain variable fragment (scFv) binding elements and other key CAR-T features, impacts multiple competitor CAR-T cell product candidates under development.

In addition to the Roberts patent, Kite’s growing intellectual property portfolio encompasses more than 150 patent assets including an exclusive license to U.S. Patent No. 7,741,465, a leading and widely significant patent directed to CAR-T constructs, developed by Dr. Zelig Eshhar and colleagues. This patent, currently under reexam by the USPTO, potentially impacts CAR-T products under development by multiple Kite competitors.